The weaver (wv) mutant mouse, the only known rodent model characterized by the association of a genetically determined degeneration of the neurons of the substantia nigra (SN) and of the cerebellar granule cells, lends itself to an analysis of fundamental issues of pathologic neurobiology which are relevant to the understanding of human neurodegenerative disorders. The strength of the proposal has been built from established work of each of the investigators who possess diverse backgrounds representing the fields of neuropathology and neuromorphology, developmental neurobiology, neurochemistry and pharmacology, molecular biology and genetics. The investigators are united by a common goal, i.e. understanding the mechanisms of nerve cell degeneration in the nigrostriatal system damaged by the genetic mutation. The cohesive effort is organized in a multi- disciplinary and highly interactive research program. We plan to investigate: the neuropathologic alterations of the nigrostriatal system using morphometric quantitative approaches combined with new developmental and genetic strategies; the transmitter neurochemistry of the SN and the molecular biological mechanisms which underlie the wv defect. Project #1 will investigate the influences of the strain associated variability of the number of midbrain dopamine neurons upon the expression of a single gene mutation affecting that neuronal population. Project #2 will characterize the embryogenesis of the SN and the postnatal degeneration of both the SN and striatum of the wv mutant. Project #3 plans to investigate the functional neurochemical correlates of the SN deficit and to study the adaptive changes which take place when various neuronal systems attempt to compensate for the deleterious effect of the mutation. Project #4 is directed to isolate and characterize the weaver gene and to study its expression during development.